Is COL11A1 p.Pro331Leu (c.992C>T) pathogenic?

COL11A1 p.Pro331Leu (c.992C>T) is classified Uncertain significance in COL11A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0786); Ultra-rare (popmax 0.0133%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL11A1 p.Pro331Leu (c.992C>T)?

COL11A1 p.Pro331Leu (c.992C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL11A1 p.Pro331Leu (c.992C>T) in the general population?

COL11A1 p.Pro331Leu (c.992C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about COL11A1 p.Pro331Leu (c.992C>T)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

COL11A1 p.Pro331Leu

c.992C>T · rs148978696 · VCV1493986

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 230 kb · p 0.038 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/74,938 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000745% 12/1,611,630 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,494
Remaining individualsnot grpmax-eligible	0.0016%	62,442
South Asian	0.0011%	91,030

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COL11A1
Protein: p.Pro331Leu
Coding: c.992C>T
MANE Select: NM_001854
dbSNP: rs148978696
Type: single nucleotide variant
Location: chr1:103022995 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.06
Residue 331: the 'nonhelical region' region

Full COL11A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL11A1 p.Pro331Ser Uncertain significance ★★ ⚠ same residue
COL11A1 c.1629+1G>A Likely pathogenic ★★ same condition
COL11A1 p.Ala1002Val Uncertain significance ★★ ⚠ same condition
COL11A1 p.Ala1160Asp Uncertain significance ★★ ⚠ same condition
COL11A1 p.Ala1383Val Uncertain significance ★★ ⚠ same condition
COL11A1 p.Ala168Thr Uncertain significance ★★ ⚠ same condition
COL11A1 p.Ala73Val Uncertain significance ★★ ⚠ same condition
COL11A1 p.Arg1173Gly Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/col11a1-p-pro331leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown